The present invention generally relates to propylisopropyl acetic acid (PIA) and propylisopropyl acetamide (PID) in their racemic and stereospecific forms, to some of their isomers and to stereoisomers thereof, for use in treatment of neurological and psychotic disorders, and affective disorders and to treat pain, including headaches and migraine pains. The present invention further relates to a method for the synthesis of PIA and PID stereoisomers. The present invention further relates to pharmaceutical compositions containing, as an active ingredient, said racemic or stereoisomer forms.
Headaches, especially in the form of migraine pain are a wide spread malady. Valproic acid (VPA), also used in antiepileptic therapy, is a drug which was approved for the treatment of migraine and has been utilized in the treatment of epilepsy for the last 25 years with a few side effects. Two major side effects being teratogenicity and hepatotoxicity, have been associated with valproate therapy. In humans, valpromide (VPD), which is also used as an anticonvulsant agent, is a prodrug of valproic acid (VPA). It was found to be more potent than VPA though it exerted more significant sedative side effects (Loscher W. and Nau H. (1985) Neuropharmacology 24: 427-435).
Isomers of VPD, such as valnoctamide (VCD-valmethamide or 2-ethyl-3-methyl pentanamide), were found to be more potent than valproic acid as anticonvulsants (Haj-Yehia A. and Bialer M. (1989) Pharm Res 6:683-9). Stereoselectivity has been shown in pharmacokinetics in man for an amide of an aliphatic short-chain fatty acid such as valnoctamide (VCD) (Barel S., Yagen B., Schurig V., Soback S., Pisani F., Perucca E. and Bialer M. (1997) Clin. Pharmacol. and Therap. 61 (4): 442-449). This work demonstrated that VCD pharmacokinetics (PK) in humans is stereoselective, with one isomer exhibiting a much higher clearance and a shorter half-life compared with the other three stereoisomers.
The present invention relates to the stereoisomers of PIA and of PID and to their isomers (such as VPD and VCA) for use in treatment of neurological and psychotic disorders, and affective disorders and to treat pain, such as head aches. Although VPA and VPD analogues (such as VCA and VCD) were implicated in the treatment of epilepsy, there is no evidence that they in their racemic form or their individual stereoisomers are active in the treatment of neurological and psychotic disorders, affective disorders and pain.
The present invention relates to racemic propylisopropyl acetic acid and propylisopropyl acetamide and their isomers in their racemic and stereospecific forms, for use in treatment of neurological and psychotic disorders, and affective disorders and to treat pain, headaches and migraines, wherein the isomers are of the compound formula I 
wherein
R1 is a methyl or ethyl group;
R2 is H, methyl or an ethyl group;
R3 is ethyl or a propyl group; and
R4 is a hydroxyl or amide group,
wherein the total number of carbon atoms in said compound is 8, provided that when R1 is a methyl group and R4 is an amide group, R2 and R3 are not ethyl, further provided that when R1 is an ethyl and R4 a hydroxyl group, only stereoisomers of the compound are referred to.
The present invention further relates to a method for the stereoselective synthesis of the 2R stereoisomer of PID and PIA comprising;
(a) synthesizing (4S)-3-(1xe2x80x2-oxopentyl)-4-benzyl-2-oxazolidinone from (4S)-benzyl-2-oxazolidinone (or other related oxazolidinone auxiliaries) and valeroyl chloride;
(b) synthesizing of Isopropyl trifluoromethane sulfonate (isopropyl triflate);
(c) synthesizing (4S,2xe2x80x2R)-3-(2xe2x80x2-isopropyl-1xe2x80x2-oxopentyl)-4-benzyl-2-oxazolidinone
(d) synthesizing (2R)-propylisopropyl acetic acid ((2R-PIA) and subsequently;
(e) synthesis of (2R)-propylisopropyl acetamide.
and to a method for the stereoselective synthesis of the 2S stereoisomer of PID and PIA comprising;
(a) Synthesizing (4R,5S)-3-(1xe2x80x2-oxopentyl)-4-methyl-5-phenyl-2-oxazolidinone from (4R,5S)-4-methyl-5-phenyl-2-oxazolidinone (or other related oxazolidinone auxiliaries) and valeroyl chloride;
(b) synthesizing (4R,5S,2xe2x80x2S)-3-(2xe2x80x2-isopropyl-1xe2x80x2-oxopentyl)-4-methyl-5-phenyl-2-oxazolidinone;
(c) synthesizing (4S,2xe2x80x2R)-3-(2xe2x80x2-isopropyl-1xe2x80x2-oxopentyl)-4-benzyl-2-oxazolidinone(4S,2xe2x80x2R)-3-(2xe2x80x2-isopropyl-1-oxopentyl)-4-benzyl-2-oxazolidinone;
(d) synthesizing (2S)-propylisopropyl acetic acid ((2S)-PIA)and subsequently;
(e) synthesis of (2S)-propylisopropyl acetamide.
The present invention also relates to pharmaceutical compositions containing as an active ingredient a racemic mixture or stereoisomers of the compounds of the general formula (I), which are useful for the treatment of neurological and psychotic disorders, and affective disorders and to treat pain, headaches and migraines.